What are the initial management recommendations for hypertension related to the Renin-Angiotensin System (RAS)?

Initial Management of Hypertension with RAS Blockers

For hypertension management targeting the renin-angiotensin system, initiate combination therapy with a RAS blocker (ACE inhibitor or ARB) plus either a calcium channel blocker or thiazide/thiazide-like diuretic as first-line treatment for most patients with confirmed BP ≥140/90 mmHg. 1

When to Start RAS Blocker Therapy

Blood Pressure Thresholds

• Start pharmacological treatment when office BP is ≥140/90 mmHg after lifestyle modifications in most adults 2
• In patients with diabetes, initiate treatment at BP ≥130/80 mmHg after maximum 3 months of lifestyle intervention 2
• In patients with chronic kidney disease (CKD), treat when BP ≥140/90 mmHg with lifestyle advice and medication 2
• For elevated BP (120-139/70-89 mmHg) with high cardiovascular risk, start pharmacological treatment after 3 months of lifestyle intervention if confirmed BP ≥130/80 mmHg 1

Specific Populations Where RAS Blockers Are Preferred

• Diabetes patients: RAS blockers may have unique advantages for initial or early treatment 2
• Metabolic syndrome: RAS blockers should be considered as preferred drugs since they improve or do not worsen insulin sensitivity 2
• CKD with albuminuria: RAS blockers are more effective at reducing albuminuria than other antihypertensive agents and are recommended as part of treatment strategy 2
• Heart failure with reduced ejection fraction (HFrEF): ACE inhibitors or ARBs are recommended as part of the treatment regimen 2

Recommended RAS Blocker Regimens

Initial Combination Therapy (Preferred Approach)

Start with a two-drug combination for most patients with confirmed hypertension (≥140/90 mmHg) 1:

Option 1: RAS blocker (ACE inhibitor or ARB) + dihydropyridine calcium channel blocker 1

• This combination is metabolically neutral and has favorable effects on organ damage 2
• Associated with lower incidence of diabetes compared to conventional treatment with beta-blockers 2

Option 2: RAS blocker (ACE inhibitor or ARB) + thiazide/thiazide-like diuretic (chlorthalidone or indapamide) 1, 3

• Preferably use as single-pill combination to improve adherence 1

Specific ACE Inhibitor Dosing Example

For lisinopril 4:

• Initial dose: 10 mg once daily in adults with hypertension
• Adjust according to BP response; usual range 20-40 mg daily
• If taking diuretics: start with 5 mg once daily
• Maximum studied dose: 80 mg (though doses above 40 mg show minimal additional benefit)

Treatment Escalation Algorithm

If BP not controlled with two-drug combination, escalate to three-drug combination 1:

• RAS blocker + dihydropyridine calcium channel blocker + thiazide/thiazide-like diuretic, preferably as single-pill combination 1

Blood Pressure Targets with RAS Blocker Therapy

General Population

• Target systolic BP to 120-129 mmHg for most adults to reduce cardiovascular risk, if well tolerated 2, 1
• If target cannot be achieved due to poor tolerance, aim for systolic BP "as low as reasonably achievable" 1
• Systolic BP goal <140 mmHg is mandatory in patients with diabetes 2
• Diastolic BP target <85 mmHg in patients with diabetes 2

Special Populations

• Diabetes: Target systolic BP to 120-129 mmHg if tolerated 2, 1
• CKD (non-diabetic or diabetic): Lower systolic BP to 130-139 mmHg range 2
• Moderate-to-severe CKD with eGFR >30 mL/min/1.73m²: Target systolic BP to 120-129 mmHg if tolerated 2

Essential Lifestyle Modifications to Enhance RAS Blocker Efficacy

Dietary modifications, particularly low-sodium high-potassium intake, enhance the BP-lowering effect of RAS blockers 5:

Sodium and Potassium

• Reduce sodium intake to <1,500 mg per day 2
• Increase potassium consumption through 8-10 servings of fruits and vegetables daily 2
• Low-sodium high-potassium diet produces greater SBP fall in those on RAS blocker therapy (-9.5 mmHg) compared to those not on therapy 5

DASH Diet Pattern

• Consume 8-10 servings of fruits and vegetables per day 2
• Include 2-3 servings of low-fat dairy products daily 2
• Adopt Mediterranean or DASH dietary patterns 1
• DASH diet shows antihypertensive effects similar to pharmacologic monotherapy 2

Weight and Physical Activity

• Aim for healthy BMI (20-25 kg/m²) and waist circumference <94 cm in men, <80 cm in women 1
• Engage in regular physical activity including both aerobic and resistance training 1
• Minimum of 30 minutes of daily moderate physical activity 2

Alcohol and Sugar

• Limit alcohol to ≤2 standard drinks per day for men, ≤1 for women (preferably avoid completely) 2, 1
• Restrict free sugar consumption, especially sugar-sweetened beverages 1

Critical Pitfalls to Avoid

Contraindications and Cautions

• Never combine two RAS blockers (ACE inhibitor + ARB) - this is contraindicated and should be avoided in patients with diabetes and generally in all patients 2
• ACE inhibitors and ARBs are contraindicated during pregnancy as they can cause fetal damage 2
• Monitor for acute eGFR decline after initiating RAS blocker therapy, particularly in renovascular disease 2

Common Management Errors

• Do not delay combination therapy in patients with confirmed hypertension ≥140/90 mmHg 1
• Do not use monotherapy when combination therapy would be more effective 1
• Do not discontinue treatment prematurely - BP-lowering treatment should be maintained lifelong if tolerated 1
• Avoid beta-blockers as initial therapy in metabolic syndrome unless specific indications exist (angina, post-MI, HFrEF), as they adversely affect insulin sensitivity and increase diabetes incidence 2

Monitoring Requirements

• Test for orthostatic hypotension before starting or intensifying treatment 1
• Monitor serum potassium and renal function after initiating RAS blocker therapy, especially when combined with diuretics
• Consider home BP monitoring to improve control and patient empowerment 1

Resistant Hypertension Management

If BP remains uncontrolled on optimal doses of RAS blocker + calcium channel blocker + thiazide diuretic 6:

• Add low-dose spironolactone (25-50 mg daily) as fourth-line agent 2, 6
• Alternatives if spironolactone not tolerated: eplerenone, amiloride, higher-dose thiazide, or loop diuretic 2
• Reinforce lifestyle measures, especially sodium restriction 2
• Screen for secondary hypertension causes (primary aldosteronism, renovascular disease, obstructive sleep apnea) 2